The present invention is directed to methods for treating atopic disorders, including asthma, eczema, sinusitis, bronchitis, and allergic rhinitis.
In the United States and other Western countries, the reported incidence of asthma is about 4-5% of the population. About half the cases develop before the age of ten and another third before the age of forty. The cost of treating asthma is enormous. Emergency room visits approximate two million a year and hospitalizations, about 500,000. Total cost of medication is estimated at one billion dollars a year, while the loss of productivity within the families of children is perhaps another billion dollars a year. The number of asthma prescriptions is thought to double per decade. In the United Kingdom, the cost of asthma treatment represented 11% of the national health budget.
The physiological hallmark of asthma is a reversible obstruction in the airways brought about by vascular congestion, thick tenacious secretions, bronchial wall edema, and smooth muscle contractions. During an attack, there is a compromise of lung function. Asthma is a chronic inflammatory disease of uncertain cause. A noticeable therapeutic change is the increased use of corticosteroids in its management.
The United Kingdom has one of the highest rates of asthma per capita of anywhere in the world. The jet stream flowing across the Atlantic keeps the British Isles wet, damp, and humid. They have an advanced xe2x80x9cwesternizedxe2x80x9d society and since dampness makes mildew grow, one sees a high incidence of asthma.
The United States, also a xe2x80x9cwesternxe2x80x9d society, has diversified weather due to its greater size. For instance, a large part of the western United States is desert. Denver and Arizona have two of the lowest areas of humidity and asthma. Asthmatics frequently move to these areas, particularly Arizona, because the extreme heat and low humidity dry dampness kill mildew and improve asthma.
In Sweden, high indoor humidity is associated with increased asthma. (See Aberg N. Asthma and Allergic rhinitis in Swedish conscripts. Clin Exp Allergy 1989;19:59-63; and Wickman M, Nordvall S L, Pershagen G. Risk factors in early childhood for sensitization to airborne allergens. Pediatr Allergy Immunol 1992;3:128-33.) Increases in asthma and allergic diseases are related to an increasingly unventilated environment. (See Aberg N, Hesselmar B, Aberg B, Eriksson B. Increase of asthma, allergic rhinitis and eczema in Swedish school children between 1979 and 1991. Clin and Experimental Allergy 1995;25:815-819.) High indoor humidity and houses damaged by dampness, owing to poor ventilation, are related to a high frequency of allergic symptoms. (See Andrae S, Axelson O, Bjorksten B, Frediksson M, Kjellman -IM. Symptoms of bronchial hyperreactvity and asthma in relation to environmental factors. Arch Dis Child 1988;63:473-8.) Environmental exposure early in life also seems important. (See Bjorksten B. Risk factors in early childhood for the development of atopic diseases. Allergy 1994;49:400-7; and Aberg N. Birth season variation in asthma and allergic rhinitis. Clin Exp Allergy 1989;19:643-8.) Dampness in homes expressed as moisture inside windowpanes, and as a noticeable dampness or mildew in the home, increased the risk of asthma, rhinitis and eczema, as well as a history of upper respiratory infections. There is a dose response relationship between the amount of moisture inside the Windows and risk. The highest risk from dampness exposure is in the first year of life.
A risk factor in allergic diseases is a parental history of allergic disease. About twice as many children have allergic disease if one parent was ever afflicted, and three times as many if both parents were afflicted, as compared with cases with no parental history (p less than 0.001). If parents smoked during the first year of life, it did not increase the risk for development of an allergic disease, not even asthma of the worst severity. The frequency of upper respiratory infections and dampness in the homes were additive, but not synergistic.
Some researchers suggested that indoor air quality and factors of a chemical or microbiological nature related to damp homes are important to the pathogenesis of allergic disease. (See Aberg N, Sundell J, Eriksson B, Hesselmar B, Aberg B. Prevalence of allergic diseases in school children in relation to family history, upper respiratory infections and residential characteristics. Allergy 1996;51 :232-237.) They also found that high indoor air humidity and dampness were strong risk factors underlying all allergic disease. Inhaled fungus seems able to cause further sensitization with resultant symptoms. High indoor air humidity and dampness might encourage fungus growth on skin and in the upper or lower respiratory tracts. He also found that recent repainting and repairing of a child""s bedroom moderately increased risk of allergic disease. Repairing and repainting of bedroom walls are notorious for exposing underlying dampness and mildew and releasing it into the bedroom environment. Finnish workers reported evidence between, and association with, mold or mildew problems in school buildings and the presence of manifest and occult asthma in the pupils. (See Taskinen T, Meklin T, Nousiainen M, Husman, T, Nevalainen A, Korppi M. Moisture and mold problems in schools and respiratory manifestations in school children: clinical and skin test findings. Acta Paediatr 1997;86:1181-7.)
Yemaneberhan, et al., working in Ethiopia, believe that the asthma and allergy being seen in developing countries may be associated with the adoption of a xe2x80x9cwesternxe2x80x9d lifestyle. (See Yemaneberhan H, Bekele Z, Venn A, Lewis S, Parry E, Britton J. Prevalence of wheeze and asthma and relation to atopy in urban and rural Ethiopia. The Lancet 1997;350:85-90.) This group found that wheeze and asthma are especially rare in the rural subsistence areas of Ethiopia where there is a reduced prevalence of these symptoms in this environment. In Jimma, which is partly westernized, self-reported asthma emerged as a clinical problem about ten years before their studies began, which is consistent with an effect of new environmental exposures. Although they could not identify the factor leading to increases in asthma and allergy, general changes in the domestic environment are likely to be involved.
Furthermore, Esamai and Anabwani found in Kenya that the prevalence of wheezing, rhinitis, and itchy rashes were similar to previous studies in Estonia. (See Esamai F, Anabwani G M. Prevalence of asthma, allergic rhinitis and dermatitis in primary school children in Uasin Gishu district, Kenya. East Afr Med J 1996;73(7):474-478.) The prevalence of asthma and allergic diseases are increasing worldwide, and it is more so in developing countries, which rapidly raise the living standard of parts of their population.
Trepka et al. studied the epidemiology of asthma, rhinitis and atopic dermatitis in Eastern versus Western populations. They found that the rate of physician diagnosed asthma and rhinitis were higher in Western Germany, though there was a tendency for slightly less atopic dermatitis in children. They speculated that if lifestyle and environmental factors play a role in this process, then the incidence of disease should converge, as the two societies become more similar. (See Trepka M J, Heinrich J, Wichmann H E. The epidemiology of atopic diseases in Germany: an east-west comparison. Rev Environmental Health 1996;11(3): 119-31.)
Hong Kong studies suggest that genetic and/or environmental factors common to the families are more important than auto aeroallergen sensitization in the pathogenesis in asthma and allergy in xe2x80x9cwesternizedxe2x80x9d Asia. (See Lau Y L, Karlberg J, Yeung C Y. Prevalence of and factors associated with childhood asthma in Hong Kong. Acta Paediatrica 1995;84(7): 820-2.) In Istanbul, atopic family history, food allergy, eczema, frequent otitis media, and sinus attacks were found to be of significance in asthma""s presence (22). When 1,500 lung experts met in Bangkok, Thailand, on Nov. 25, 1998, they agreed that the breath-robbing disease is on the rise in many countries, especially among children, and that a westernized life style was a major risk factor.
The International Study of Asthma in Childhood (ISAAC) studied 463,801 children, aged 13 to 14 years, situated in 155 collaborating centers in 56 countries. (See Lewis, S. ISAACxe2x80x94a hypothesis generator for asthma? The Lancet 1998;351:1220-1224; Asher M I, Keil U, Anderson H R, Beasley R, Crane J, Mrtinez F, Mitchell E A, Pearce N, Sibbald B, Stewart A W, Strachan D, Weiland S K, Williams H C. International study of asthma and allergies in childhood (ISAAC): rationale and methods. Eur Respir J 1995; 8:483-491; and Writing Group and Steering Committee. Worldwide variation in prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and atopic eczema: ISAAC. The Lancet 1998;351:1225-32.) One finding of the study was that countries with the lowest asthma rates, including several Eastern European countries, Indonesia, Greece, China, Taiwan, Uzbekistan, India, and Ethiopia, also had the lowest prevalence of allergic conjunctive, rhinitis and atopic eczema.
ISAAC found that the highest prevalence for asthma symptoms was mainly in English speaking centers and mainly in Western countries. These findings raised the possibility that environmental factors relating to living conditions in these countries are important. By contrast with the asthma findings, the highest prevalence of allergic rhinitis symptoms were reported from different centers in the world. Several centers with the highest symptom prevalence were not represented among the countries with the highest asthma prevalence. ISACC suggests that the major risk factors for these related disorders may differ or may involve different latency periods and time trends.
Allergic rhinitis may be missed in children, if some of the classic symptoms or signs are missing or they have indolent infections. A further problem is that xe2x80x9ceczemaxe2x80x9d in one set of countries may be brushed off as simple xe2x80x9cdry skinxe2x80x9d in others. Some children may have been taught to consider so-called xe2x80x9cdry skinxe2x80x9d as nothing to worry about, and certainly not eczema. Sociological conditioning in different cultures as to what is normal or not may play some part in ISMC""s findings.
When self reported symptoms of more than one atopic disorder were taken in to account, the highest prevalence were again observed in English speaking, westernized countries. ISMC also found that remarkable differences, and widely different prevalence, occurred between centers with populations of similar ethnic origins in countries such as China, (including Taiwan and Hong Kong), India, Italy, and Ethiopia. Once again these phenomena may have multiple causes that could in part be explained by the influence of Western culture.
Eczema is seen throughout life with an age distribution similar to that of asthma. Investigators have drawn attention to a seeming, but not understandable relationship between these two entities. (See Daniels Se, Bhattacharrya S, James A, Leaves N I, Young A, Hill M R, Faux J, Ryan G F, Ie Souef P N, Lathrop G M. A genome-wide search for quantitative trait loci underlying asthma. Nature. Sep. 19, 1996. 383(6597)L247-50.) In rich xe2x80x9cwesternizedxe2x80x9d countries, both are increasing. Various topical corticosteroids and antihistamines are commonly used in treatment. As with asthma, systemic corticosteroids are limited to severe exacerbations. Usually oral corticosteroids clear the skin only briefly. Stopping their use usually results in a return of the dermatitis. As with sinusitis and asthma, systemic corticosteroids bring about amelioration, but not cure. The use and effects of corticosteroids in the three diseases is similar.
Sinusitis, like eczema and asthma, is considered an inflammatory disease, the prevalence of which is rising. Possibly, 14% of the population is affected. Antibiotics, decongestants, antihistamines, and surgery are often used in its treatment, while corticosteroids are used to control it. (See Horner W E, Helbling A, Salvaggio J E, Lehrer S B. Fungal allergens. Clin Microbiol Rev 1995;8(2):161-179.)
The present invention is based on the discovery that eczema, allergic rhinitis and asthma result as a progression of the same disease process. This illness often first manifests itself as a fungal disease of the skin, which can become complicated by bacterial infection (Stage I).
Stage II is the inhalation, infection and sensitization of the nasal passages by the skin infection setting up an xe2x80x9callergic rhinitis.xe2x80x9d As time passes and with only symptomatic treatment, the mixed infective process increasingly damages the upper airway system and a chronic sinusitis may occur.
Stage III is a spreading of the infection into the airways and lungs and its sensitization by the same infective process, resulting in inflammatory airways obstruction, chronicity and the development of a myriad of secondary changes in the respiratory system and body.
More specifically, there are two parts to Stage I of the syndrome. The skin develops a fungal infection, which is mistakenly called xe2x80x9cdry skinxe2x80x9d (Stage IA). In the second part of the first stage this fungal infection spreads, becomes noticeably infected with bacteria, and is called xe2x80x9ceczemaxe2x80x9d (Stage IB). The presence of either can result in the development of allergic rhinitis (Stage II A) and/or sinusitis (Stage II B).
Mildew, a type of fungi, usually results in situations when a normally dry surface becomes chronically wet. If a person""s skin becomes chronically wet, the result will be infestation with fungi. Many experience this between their fourth and fifth toes when they do not dry off properly on a continual basis. Water normally evaporates off the skin even when not dried off with a towel. However, when water collects between the toes where air cannot reach it well, thereby keeping this area chronically wet, a condition we call xe2x80x9cathlete""s footxe2x80x9d or tinea pedis may develop. It may be mistaken for xe2x80x9cdry skin,xe2x80x9d but it is actually a dermaphytic fungal infection.
When various substances such as lotions, moisturizers, oils, ointments, Vaseline, cocoa butter, greases, skin softeners and many baby care products are put on the skin, they can make the skin wet for weeks causing mildew to form on it. Most people mistake the mildew for so-called xe2x80x9cdry skin.xe2x80x9d Soon to be patients see the white, flaky mildew on their skin, and assume that the skin is xe2x80x9cdry.xe2x80x9d This results in their applying more lotion, which results in more and more mildew. Gradually the deposits of mildew become more obvious in various areas of the body, such as the heels, elbows, kneecaps, finger-webs, cheeks and scalp. Medically, when skin becomes chronically wet and infected with fungus, it is called tinea corporis (tinea of the body), tinea capitis (head), tinea cruris (groin), tinea manuum (hands), and tinea barbae (face). Once tinea is established in a body area, it requires treatment with a systematic antifungal drug, like itraconazole or terbinafine to get rid of it. If the infection is not treated in its entirety and completely cured, it tends to reoccur.
Giving cortisone or its derivatives merely treats the symptoms, but does not cure the infection. As a result, the lesions live on, causing chronicity and gradual spread over the body, particularly, if the daily application of lotions and moisturizers continues. This disease is then called xe2x80x9ceczemaxe2x80x9d (Stage 1B).
The inventor has treated numerous patients with xe2x80x9ceczemaxe2x80x9d and discovered that a large majority of the patients are cured by the use of oral antifungals for a period of time and/or antibiotics, preferably a combination of an antifungal and antibiotic. An oral antihistamine may be also be administered to help control itch, particularly in the early weeks of treatment. A part of this treatment is a cessation of all application of emollients, such as lotions, moisturizers, and the like. In one embodiment, the invention is directed to a method for treating eczema comprising reducing the application of emollients and administering an antifungal and/or an antibiotic.
Stage II is the development of xe2x80x9callergic rhinitisxe2x80x9d (Stage IIA), which can, overtime, develop into an associated chronic sinusitis (Stage IIB). Itching of the conjunctiva, nose and pharynx, episodic rhinorrhea, sneezing, with obstruction of the nasal passages occurs. An incidence rate of about 7% is seen in North America. It is most common in childhood and adolescence. Swelling of turbinates and mucous membranes with obstruction of the sinus ostia and Eustachian tubes can cause secondary infections of the sinuses and middle ear. Nasal polyps often arise concurrently with edema and/or infection within the sinuses and increase obstructive symptoms.
If a person has fungus growing on their upper torso, face and/or scalp, it is just a matter of time before it would be inhaled into the nose and upper airways. Since it will be inhaled onto a wet surface, it is likely to take hold, perhaps causing a primary infection, a sensitizing reaction or a further sensitization to the fungus or perhaps all three. What begins as rhinitis can cause secondary sinusitis.
A useful first step in the treatment of sinusitis is the endoscopic removal of polyps and inflammatory material to establish aeration and drainage of involved sinuses, followed by administration of an antifungal agents along with reduction of application of emollients.
More specifically, when sinusitis has been present for years, the inventor has noted that a fungal infection may be part of the process and can cause xe2x80x9cpeanut butterxe2x80x9d like plugs. Within the sinuses there are strategic areas such as the meatus in the ethmoid complex that are narrow. If these become blocked, as happens in infections, then obstructive sinusitis occurs. A fungus infection in an already damp environment tends to chronicity, making it easy to see how a fungal infection could cause obstructive sinusitis, with its resultant pathology.
These xe2x80x9cpeanut butter likexe2x80x9d plugs should be surgically removed, such as by camera-controlled laparoscopic sinus surgery. However, for fungal sinusitis to be properly cured, the further inhalation of fungus from outside the nasal passages and sinuses must stop, thereby requiring the reduction of application of emollients. Additionally, effective control of sinusitis can result in improvement of asthma.
Stage III is a spreading of the infection into the airways and lungs and its sensitization by the same infective process, resulting in xe2x80x9cbronchitisxe2x80x9d(Stage IIIA) and/or xe2x80x9casthmaxe2x80x9d(Stage IIIB). Clinically, chronic bronchitis is often an early part of the onset of reversible obstructive airways disease. In another embodiment, the invention is directed to a method of treating bronchitis and/or asthma. The method comprises administering an antifungal and/or an antibiotic for a period of time and reducing the administration of emollients over that period of time.
The methods of the present invention, which involve the reduction or cessation of the administration of emollients is consistent with the knowledge that, as the level of income rises and populations become more xe2x80x9cwesternizedxe2x80x9d, atopy takes hold. Specifically, as disposable income increases, the sale of xe2x80x9cluxuryxe2x80x9d items, including perfumes, shampoos, cosmetics and skin care preparations, increases. The poor in rural areas and less-developed countries cannot afford such items. Nor are such people subject to the propaganda and salesmanship of the cosmetic industry, glossy magazines, and television. Additionally, the theory of the invention tends to explain why parental asthma is a risk factor, since parents who put lotions and the like over their own skin tend to do it to their children.
In one embodiment, the invention is directed to a method for treating an atopic disorder in a patient. The method comprises administering to the patient an effective amount of at least one of an antifungal and an antibiotic over a period of time. The method further includes reducing over the period of time the application of emollients to the patient by at least about 50%, relative to the amount of application of emollients prior to treatment.
In another embodiment, the invention is directed to a method for treating asthma comprising administering to the patient an effective amount of an antifungal over a first period of time and administering to the patient an effective amount of an antibiotic over a second period of time. The method further comprises reducing the application over a third period of time of emollients to the patient by at least about 80%, relative to the amount of application of emollients prior to treatment.